Achieving an effective concentration of a drug or such by oral administration or injection is more difficult in the brain than in other organs because of the presence of the blood-brain barrier. While an effective drug concentration may be ensured by administering a large dose, this would mean infusing the drug in excess amounts into peripheral blood, which would cause adverse effects such as kidney and liver damage. Therefore, it became necessary to develop a system that selectively transports drugs to the brain. Numerous studies are being carried out in this respect. Most of such research and development involve efforts to enhance brain localization through chemical modification of the drug itself by utilizing a property of cerebrovascular endothelial cells—the higher the lipid solubility of a substance, the more easily it passes through the blood-brain barrier. Such a method improves drug localization in the brain by several folds at best, which is on the whole, no more than an error range. In the brain, contrary to peripheral organs where substances permeate through the intercellular spaces of vascular endothelial cells, the intercellular spaces of cerebrovascular endothelial cells form special structures called tight junctions and hardly allow permeation of blood components through them. Therefore, transport of substances to the brain must be carried out by permeation after chemical modification of the substances to make them lipid-soluble and directly integratable into the cell membrane. More specifically, this method makes substances permeate directly into cells as there is no alternate route for substance transport to the brain, different from peripheral organs. However, since this mechanism is different from the usual, the efficiency is several thousands to tens of thousands times lower. Therefore, this method cannot be referred to as brain-specific drug transport.
With recent technological advances, techniques that target membrane surface proteins expressed on cerebrovascular endothelial cells have been developed. In particular, it is effective to utilize the function of proteins called transporters for incorporating drugs into the brain. Since hardly any substances permeate into the brain through intercellular spaces as described above, amino acids and sugars in blood are specifically transported into the brain by binding to transporters expressed on the blood-brain barrier. Transferrin receptors are transporter molecules that transport proteins called transferrins to the brain. Transferrins supply metal ions to metalloenzymes which are necessary for brain activity. It was reported that using specialized antibodies to target transferrin receptors could increase the brain localization of drugs by several tens to approximately a hundred times (see Non-Patent Document 1).
However, transferrin receptors are expressed not only in cerebrovascular endothelial cells, but also in liver and kidneys at an even larger quantity. Therefore, when this system is used, along with an increase in the amount of drug transported to the brain, the drug is also introduced into the liver and kidneys. Thus, this can hardly be called brain-specific transport. In addition, although there have been reports on systems that utilize several transporter molecules and antiporter molecules such as P-glycoproteins, none of them have been confirmed to be effective.
Furthermore, methods that utilize special functional peptides have been recently developed. These peptides are called PTD sequences, and were identified as peptide sequences necessary for HIV tat gene products to translocate into the cell nucleus. These peptides pass through not only the nuclear membrane, but all kinds of cell membranes (see Non-Patent Document 2), and can therefore be distributed to organs throughout the entire body when injected into blood. PTD peptides can transport substances into the brain because they can pass through the cell membrane of cerebrovascular endothelial cells. However, although both PTD sequence-mediated transfer through the cell membrane and permeation from the intercellular space are effective in peripheral organs, the latter permeation is absent in the brain, making substance permeability much lower than in other organs. Therefore, this technique also cannot be brain-specific.
Meanwhile, molecules that regulate the organ specificity of vascular endothelial cells have been recently reported. Depending on the organ's role and specificity, each organ in the body has different nutritional requirements and different degrees of requirements for various factors supplied by blood. It is gradually becoming clear that vascular endothelial cells distributed in organs have slightly different characteristics depending on where they exist. Furthermore, vascular endothelial cells serve as direct contact points with inflammatory cells and immune cells present in blood, and control the invasion of these cells during inflammation and morbid conditions. Invading cells then accumulate at lesions by recognizing inflammatory homing receptors that appear during inflammation, as well as tissue-specific vascular endothelial cell marker molecules (called cellular zip codes). Although their roles are still unclear, these cell markers are attracting attention because targeting of these molecules can at least allow targeting of a molecule of interest up to vascular endothelial cells of an organ (Non-Patent Document 3). However, although this method can target a molecule of interest up to vascular endothelial cells of each organ, systems for introducing the molecule into the parenchyma of an organ must be devised.
(Non-Patent Document 1) Ningya Shi and William M. Pardridge, Noninvasive gene targeting to the brain. Proc. Natl. Acad. Sci. USA, Vol. 97, Issue 13, 7567-7572, Jun. 20, 2000
(Non-Patent Document 2) Steven R. Schwarze, Alan Ho, Adamina Vocero-Akbani, and Steven F. Dowdy, In Vivo Protein Transduction: Delivery of a Biologically Active Protein into the Mouse. Science 1999 Sep. 3; 285: 1569-1572.
(Non-Patent Document 3) Renata Pasqualini, Erkki Ruoslahti, Organ targeting in vivo using phage display peptide libraries. Nature Vol. 380, 28, Mar. 1996.